Fortunately, there are products available to the professional that provide effective topical anesthesia, making use of safe and effective active principles integrated into drug delivery systems that allow them to penetrate the skin.

In this article I will deal with the phenomenon of pain, and why it is to everyone’s advantage to keep pain well under control. I will also outline the mechanisms of action and types of local anesthetics and counterirritants, and the drug delivery systems into which these products are formulated to maximize their availability to the target tissue (the pain receptors buried deep in the dermis).

The importance of pain control

How often have we heard the words: “No Pain, No Gain,” “Pain comes with the Territory” or, “If she really wants to get rid of hair she’ll put up with the pain.” And electrologists have been heard to say, “My treatment does not hurt (that bad),” and “I’ve always done it without topical anesthetic.” While these assertions and assumptions may be true for some clients and some electrologists, in general there is much to be gained by insuring that the client is as comfortable as possible during treatment.

First of all, pain is not necessary to achieve the goal of helping the client get rid of unwanted hair. Therefore, the humanitarian, compassionate thing to do is to recommend to the client that she use a safe and effective topical anesthetic. You can’t promise the client that she won’t feel anything, because that is a set-up for failure, but you can certainly say that the edge will be taken out of it.

I want to emphasize that the use of a topical anesthetic is something that you recommend that your client should do – not something that you decide to do on your client. The administration of pharmaceutical drugs, even over-the-counter drugs, is considered a medical act. Only doctors, registered nurses (under doctor’s orders) and parents of minors (Doctor Mom) are allowed to do that. The decision to use a topical anesthetic, an aspirin, or anything else, must be the client’s.

When the client is more comfortable, so are you. It allows you to do a more precise, complete job, while increasing your professional and personal satisfaction. The client will allow longer treatment times, will be more likely to complete her series of treatments and less likely to skip appointments. Best of all, it will lead to the best word-of-mouth referrals. Finally, remember that human beings will do more to avoid pain than to gain pleasure!

 The phenomenon of pain

In order to experience pain, two events need to happen: (a) a sensitive fiber in the skin (or elsewhere) is stimulated, and (b) the brain receives the message that this has happened.

The transmission of the message – from the site of the stimulus, to the brain – is called “the conduction of the nervous impulse.” Normally, in a resting fiber, there are sodium (Na⁺) ions in the outside, and potassium (K⁺) ions in the inside. When the fiber is stimulated it causes a special “gate” (a pore formed by proteins) in the nerve membrane to open, allowing sodium ions to come in and potassium to flow out.¹ This causes the next gate to open, then the next, and so on. The best analogy I have is the “wave” that people can make in stadiums, where one person puts her arms up, then the person sitting next to her, and so on. Nothing really moves, but the message or wave goes fast from one end of the stadium to the other. This is similar to the way a nervous impulse is transmitted to the brain.

Mechanism of action
of local anesthetic

Local anesthetics are substances capable of blocking the conduction of the nervous impulse. They bind to and block the sodium channels in the nerve membrane, therefore the “gates” cannot open. The message that painful stimuli occurred is not transmitted to the brain. These effects are reversible; after a while the drug diffuses away into the bloodstream and the nerve is capable of responding again.

It is interesting to note that local anesthetics affect all the nerve fibers present in the skin, but at different rates, inversely proportional to their diameter. Luckily for the patient, the smallest (thinner) fibers are affected first, and these are the sensitive (pain conducting) fibers. The second ones to be affected are the temperature sensors, which respond to heat or cold. The third ones are the touch sensors. And finally, there are the deep pressure fibers.^1,2 This order of loss of sensation – pain, heat or cold, touch, deep pressure – explains why touch is not a good indicator for numbness: we can feel that someone is touching or pressing an anesthetized area, even though the pain sensation is mostly gone.

There are other substances, which are not topical anesthetics, that can interfere locally with the phenomenon of pain. They are known as counterirritants, and are widely used in pain-relieving preparations. Common examples are menthol, camphor, capsaicin, and methyl salicylate. They act by a different mechanism: they increase the blood supply to the area, creating a sensation of warmth (sometimes preceded by coolness). This interferes with the transmission of impulses by the smaller fibers, because it “confuses” the pain receptors. Doctors use the same principle when they pinch, pat and/or shake the skin prior to an injection: the strong touch and pressure sensation does not allow the patient to fully respond to the painful stimuli. The application of cold is yet another example of this “interference” method to reduce the pain response.

Drugs such as aspirin, acetaminophen, ibuprofen, or the opioids (morphine, codeine) are also analgesics, but they act on the brain, as opposed to the local anesthetics that act on the nerves. They bind to brain pain-receptors and increase the pain threshold. In other words, they reduce the ability of the brain to respond to the pain stimuli.

The “caine” family of anesthetics

The most commonly used topical anesthetics belong to the same chemical group, the “caine” family. They are all chemical variations of the most famous (or infamous) “caine” of all, cocaine.

Cocaine is a naturally occurring substance, used since ancient times by the indigenous people of the highlands of Peru, not for its anesthetic properties, but for its ability to stimulate the central nervous system and create sensations of euphoria, well-being, and increased endurance. The Peruvian Indians chew it, and experience numbness in the mouth, including the tongue and lips. In the 1800s, famed psychiatrist Sigmund Freud and his colleagues became interested in cocaine. Freud used it to wean a colleague from morphine – with great success – but at the cost of creating the first well-documented case of cocaine addiction.

The search for better alternatives to cocaine, led to the synthesis of many topical anesthetics. They belong to two closely related groups within the caine family: the ester group, comprising derivatives of para-amino-benzoic acid (PABA), and the amide group. They differ in stability, potential to cause allergic reactions, solubility in water and lipids, potency, duration of action, and systemic toxicity.

The members of the ester family are susceptible to hydrolysis (breakage of the molecule by water). This results in the production of the parent compound, PABA, which causes allergic reactions in a wide group of people. The amide types don’t hydrolyze and are rarely allergenic.³

In topical anesthesia, potency and duration of action are correlated with lipid solubility (as long as the molecule remains to some extent water-soluble, since water solubility is required for diffusion to the final site of action). Tetracaine, bupivacaine and etidocaine are the most liposoluble – and therefore the most potent – and have the longer duration of action. Unfortunately, these agents are also the most toxic.

The best balance of potency, lipophilicity, toxicity, and duration of action, is achieved with lidocaine, prilocaine and mepivacaine. Of these, lidocaine is the most potent, and consequently the most widely used topical anesthetic. It has a long history of use, since it was first introduced in 1948.

The toxic effects of topical anesthetics occur only if they reach the systemic circulation in excessive amounts. These effects are more likely to occur when the agents are injected (as in dental applications) than when they are applied to the skin. These compounds have a good safety margin and adverse reactions are quite rare. When toxicity occurs, it affects mainly the cardiovascular and central nervous systems.^1,2

Effects on the cardiovascular system may include bradycardia (slow heart beat), hypotension (low blood pressure) and cardiovascular collapse leading to cardiac arrest.³ Effects on the central nervous system may include sleepiness, light-headedness, visual and auditory disturbances, and restlessness. At higher concentrations, nystagmus (rapid eye movements) and shivering may occur. Finally, tonic/clonic convulsions, followed by central nervous system depression and death, may occur with all local anesthetics, including cocaine.

Other topical anesthetics

Certain alcohols and ketones exhibit local anesthetic properties, among them are benzyl alcohol, phenol, resorcinol and juniper tar. They all differ in potency and toxicity, and in general, are less active and/or more toxic than the members of the “caine” family.

FDA regulations
for topical anesthetics

In the U.S., the federal Food and Drug Administration (FDA) regulates the concentration of each active principle that can be formulated in an over-the-counter (OTC) product. These products can be sold without a medical prescription.⁴

Products that contain more than one caine active principle are not allowed in the U.S. without a prescription, and EMLA cream, which contains a combination of Lidocaine (2.5%) and Prilocaine (2.5%), is not found as an OTC product. On the other hand, EMLA is readily available without a prescription in Canada and some other countries. Benzocaine preparations may contain up to 20% of that drug, whereas the maximum concentration of Lidocaine allowed in the U.S. for OTC use is 4%. This reflects the relative potency of the drugs.

The FDA does allow combinations of actives from the caine family with actives from the alcohols and ketones groups as well as from the counterirritants group, but the Agency limits the concentrations of each active that can be used.

Drug delivery systems

Up to this point in our discussion of topical anesthetics, we have focused on the identity of the active principle. However, this is only one part of an efficacious topical anesthetic. The active principle needs to be delivered from the surface of the skin where it is applied, to its site of action; i.e. the membrane of the sensitive fibers buried deep in the dermis. The mere presence of an active in a product is not assurance of performance.

The role of a delivery system is to ensure that the right concentration of the right chemical is reaching the right site in the body for a sufficiently long period of time. An ideal topical anesthetic would have a very short lag time (time between application of the product on the skin and onset of effective numbness), achieve relevant concentrations at the nervous membrane so as to provide deep anesthesia, and be able to maintain that concentration for an adequate period of time. In anesthetics jargon one would say an ideal anesthetic has “a quick onset, good depth, and prolonged duration of effect.”

There are considerable obstacles to overcome to achieve this, and to understand them it is necessary to consider the structure of the skin and the routes of penetration through it.

The skin consists of three layers: the outermost layer being the stratum corneum. This is the greatest barrier to skin penetration for any substance. A useful analogy is a brick wall: it is composed of 15 to 40 overlapping layers of non-viable keratinocytes, the “bricks,” surrounded by a “mortar” of lipids.

Below the horny external layer is the epidermis, a thin layer of living keratinocytes, and deeper still is the dermis, a loose tissue with higher water content where collagen and elastin fibers intertwine with fibroblasts, blood vessels and nervous fibers. Below the dermis lies the subcutaneous tissue, rich in blood supply and fat cells. The sensitive fibers are located deep in the dermis, and therefore a topical anesthetic needs to reach this area to be effective.

Skin penetration routes

There are three pathways available to any molecule attempting to cross the stratum corneum: (1) shunt pathway – passage through the openings of the hair follicles and sudoriferous (sweat) glands; (2) intercellular route – diffusion through the intercellular spaces of the cornified keratinocytes (through the mortar); and (3) transcellular route – diffusion through the cornified cells themselves (through the bricks).

The shunt pathway is of relatively minor importance because its openings are only a very small fraction of the surface area of the skin. This route is used by all molecules in the initial phase of skin penetration, before diffusion starts. Small, charged molecules, and high molecular weight non-charged molecules (that cannot diffuse) can only use this route, but their rates of penetration are small.

The intercellular space in the stratum corneum is filled with lipid bilayers alternating with thin aqueous layers. Only water and some alcohols are able to use the intercellular route.

The transcellular pathway is the route followed by the majority of molecules. They have to cross directly through the dead cornified cells, composed of keratin (protein) fibers interspersed in a lipid matrix.⁵

The lipids that pervade the stratum corneum constitute a barrier to any molecule that is not liposoluble. Molecules that are only soluble in water are not able to penetrate, and the opposite is true: the more lipophilic a molecule is, the more easily it will penetrate.^6,7,8

Once a molecule has crossed the stratum corneum, it faces practically no more resistance in reaching the viable epidermis, which is an environment rich in water. However, a molecule needs to possess solubility in water, or change into a form that has it, or else it will not be able to penetrate further. The dermis is similar to the epidermis, in the sense that it is mainly a water-rich area.

Dermal versus transdermal
drug delivery

Another very important issue relating to drug delivery to the skin (dermal delivery) is the effect of blood uptake. Once the drug has crossed the stratum corneum, the main barrier, it is free to go deeper, and it reaches the epidermis and dermis, which possess an abundance of capillary blood supply. Drugs that penetrate the capillaries are taken away into the systemic circulation. This drug may never reach the intended site in the skin; in the case of topical anesthetics, the sensitive fibers. Instead the drug may reach other organs in the body where its effects are not desired (systemic side effects or toxic effects).

On the other hand, when the skin is used as a portal for the administration of a drug to an internal organ (transdermal delivery), as it is in the case of a nicotine or hormone replacement patch, this blood uptake is desired and crucial.

Most pharmaceutical drugs are weak bases and this means they can be formulated either as their salts (example: a hydrochloride salt of a drug) or as their free bases. Free bases are lipophilic and can penetrate the stratum corneum whereas the salt forms do not and require special delivery systems to do so.

The melting point of a drug is also important because it correlates with its ability to penetrate the skin. The lower the melting point, the better the penetration. This is a factor that is intrinsic to the drug, and cannot be changed by the formulator. However, in rare instances, a mixture of drugs, or drugs and inert ingredients, form what is called a eutectic mixture. These mixtures have a lower melting point than either component by itself, and as a result, the combination has better skin penetration than its parts alone.

The diffusion rate of any substance through a membrane or barrier (including the stratum corneum) is proportional to the concentration gradient across that membrane. This simply means that the higher the concentration of drug in the vehicle, the higher the rate of penetration.

If the drug is formulated in a thick, sticky (viscous) substance, it must first diffuse through this vehicle before it can make contact with the skin. This will slow down the rate of penetration, especially at the beginning (will increase the lag time). The same is true when the drug is encapsulated in a polymer of any kind, or inside multilayered lipid vesicles like liposomes. Also, if the drug is present in an insoluble form (example: a solid suspended in the vehicle), it has to dissolve first in the vehicle, and then cross it, before it can even begin to penetrate the skin. This may slow down the process too. Ideally the drug would be dissolved at high concentration in the vehicle.

Skin permeation enhancers

Skin permeation enhancers are substances that temporarily and reversibly increase the permeability of the stratum corneum. The types we are most likely to be familiar with are the transdermal permeation enhancers, which are intended to facilitate penetration into the systemic circulation. They are excellent solvents for a wide range of drugs, have good affinity for the stratum corneum, and increase blood circulation in the skin. They are not useful when the intended site of action is in the skin.

Useful permeation enhancers for dermal drug delivery act by a variety of mechanisms:⁹

– substances which have a great affinity for the stratum corneum and that are good solvents for the drug increase drug penetration. Examples are certain low molecular weight alcohols and ethers.^10,11

– substances that increase the fluidity of the stratum corneum lipids. This group is extensive and includes certain fatty acid esters, fatty alcohols, glycerin derivatives, non-ionic surfactants and many more.¹²

– substances that modify the level of hydration of the stratum corneum. Many substances penetrate partially the horny layer and then attract water to it, increasing its permeability. Examples are certain carbohydrates, both simple and polymeric, glycerin and certain derivatives, and many more.¹⁴

Vasoconstrictors (agents causing constriction of blood vessels) like epinephrin are not permeation enhancers, but they can be useful additives to the formulation since they reduce blood flow, and thus reduce loss of drug to the systemic circulation. Vasoconstrictors work best when the local anesthetic is delivered directly into the dermis by injection. They penetrate poorly the stratum corneum, so their efficacy in topical preparations is questionable.

Delivery from lipid vesicles

We all know that water and fats don’t mix. When we want to clean our dishes, we add a touch of detergent, right? When we know this, we already know most of the chemistry that we need to understand “lipid vesicles delivery systems.” The detergent is what is called a surfactant: meaning “it acts on the surface.” In this case, the surface is between water and lipid. It allows the two to mix and it forms a little vesicle (see Fig. X ). What is interesting is that these vesicles can be loaded with therapeutic drugs, and it helps them penetrate the stratum corneum.

The surfactants come in many varieties, but they all share the property of having a polar “head” that mixes well with water, and a fatty “tail” that mixes well with lipids. The surfactant concentrates in the surface of the droplet, and makes it stable. There may be only one layer of surfactant, in which case the inside of the droplet may only contain lipid-loving material. Alternatively, the surfactant may form a sort of “sandwich” – head-tail-tail-head – called a bilayer; and in this case the inside of the vesicle can contain both water-loving and lipid-loving drug.

There may be vesicles with only one bilayer, or with many bilayers. The type of surfactant and the method of preparation influence the number of layers that the particle will have.

Liposomes are made with lecithin, a phospholipid surfactant, and are big vesicles with many bilayers.

Niosomes are made with non-ionic surfactants. They are smaller, sometimes with only one bilayer.

A lot of research has been dedicated to lipid vesicles^{13,14,15,16,17}. When drugs are loaded into them, they penetrate to the stratum corneum level faster than the drugs by themselves. They do not penetrate deeper though; many studies have shown that lipid vesicles accumulate and disperse into the upper levels of the stratum corneum, without further penetration into the epidermis, dermis or deeper. No transport of lipids takes place across whole skin.

Commercial skin permeation
and delivery systems

EMLA® cream (Astra Pharmaceuticals), contains 2.5% lidocaine and 2.5% prilocaine. Lidocaine and prilocaine combine to form a eutectic mix, with better penetration than either component by itself.

ELA-max® cream (Ferndale Laboratories), contains 4% lidocaine salt, delivered from phospholipid liposomes.

Topicaine® (ESBA Laboratories), contains 4% lidocaine base, in a gel microemulsion. The lidocaine base is delivered both from the continuous (gel) phase, that contains skin permeation enhancers, and from the lipid microvesicles dispersed in it.

Physically enhanced permeation

There are a variety of external ways to facilitate skin penetration of a topically applied product. Among them are: exfoliation or peeling of the skin, defatting with lipid solvents, increasing the skin temperature, increasing the skin moisture, and the application of an electric current (iontophoresis). Many of these methods may be irritating to the skin, uncomfortable for the patient, time-consuming, or combinations of these.

A common method to help the penetration of a topically administered medication is to cover the application area with a dressing or patch of non-porous material such as plastic wrap. The dressing raises the skin temperature and traps perspiration. The increase in temperature causes the lipids in the stratum corneum to be more fluid, and therefore more permeable. The increase in moisture also makes the stratum corneum to be more permeable, because water is a plasticizer of keratin and a component of the intercellular route. On the other hand the increase in temperature is not so advantageous for local delivery, since it increases the blood supply and hence the amount of drug lost to the general circulation.

 CONCLUSION

The subjects of topical anesthesia and drug delivery systems are vast and complex, so by nature this review cannot be by any means exhaustive. My hope in writing it was to present the main ideas in an organized way so the modern practitioner can make a more educated choice of topical anesthetic products and methodology to use in their practice.

REFERENCES